This proposal is to promote the initiation and the development of a multi-disciplinary, thematic Center of Excellence in Diabetes and Obesity Research at the University of Louisville. The primary objective and the central focus of the Center are to enable, promote, and support scientific research related to the cardiovascular causes and consequences of diabetes and obesity. The second major aim of program is to provide mentoring and guidance to junior investigators in the Center, with the overall goal of discovering new tierapies for the treatment and prevention of diabetes and obesity. Specific objectives of the program are to: [1) Build and develop a thematic multi-disciplinary research center focused on diabetes and obesity research; (2) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease (3) Expand and bridge on-going research programs to integrate current expertise into a thematically coherent program (4) Promote collaborative interactions to build complementary individual and multi-investigator research projects; (6) Foster research careers of junior investigators leading to their development as independent principal investigators; (7) Build upon our existing research capabilities and core facilities to provide the state-of-the-art infrastructure support; (8) Develop a nationally-competitive program that will attract the best clinical cardiology fellows, graduate students, postdoctoral fellows and new faculty; and most importantly to discover new and effective means for preventing and treating diabetes and obesity. The five related projects of junior investigators for the first phase of the Center are to: (1) delineate the contribution of oxidative stress to hyperglycemic injury and test whether antioxidant interventions prevent vascular injury in diabetes; (2) to investigate whether hyperglycemia impairs the cardiac reparative potential of mesenchymal stem cells and whether transplantation of stem cells with greater potential for cardiac repair will result in greater improvement of function in diabetic hearts following infarction; (3) delineate the mechanisms contributing to premature senescence and death of cardiac progenitor cells leading to non-ischemic diabetic cardiomyopathy; (4) examine whether hyperglycemic stimulation of foam cell formation is mediated by ER stress and the unfolded protein response and if drug that act as chemical chaperone ameliorate accelerated atherogenesis in diabetic animals; and (5) identify the regulation of high glucose-triggered inflammatory signaling (NF-KB activation) by specific micro RNAs. These investigations will be supported by establishing state-of-the-art core facilities in confocal microscopy, flow cytometry, cardiovascular pathology, animal models and imaging and function. We believe that a Center focused on diabetes and obesity will add to the academic success of the University and will have a positive impact on the field of diabetes and obesity research in the nation. [unreadable] [unreadable] [unreadable] [unreadable]